Design, Synthesis, and Structural Characterization of Novel Diazaphenothiazines with 1,2,3-Triazole Substituents as Promising Antiproliferative Agents

Molecules. 2019 Nov 30;24(23):4388. doi: 10.3390/molecules24234388.

Abstract

A series of novel 1,2,3-triazole-diazphenothiazine hybrids was designed, synthesized, and evaluated for anticancer activity against four selected human tumor cell lines (SNB-19, Caco-2, A549, and MDA-MB231). The majority of the synthesized compounds exhibited significant potent activity against the investigated cell lines. Among them, compounds 1d and 4c showed excellent broad spectrum anticancer activity, with IC50 values ranging from 0.25 to 4.66 μM and 0.25 to 6.25 μM, respectively. The most promising compound 1d, possessing low cytotoxicity against normal human fibroblasts NHFF, was used for gene expression analysis using reverse transcription-quantitative real-time PCR (RT-qPCR). The expression of H3, TP53, CDKN1A, BCL-2, and BAX genes revealed that these compounds inhibited the proliferation in all cells (H3) and activated mitochondrial events of apoptosis (BAX/BCL-2).

Keywords: 1,2,3-triazole ring; BAX/BCL-2 ratio; CDKN1A; H3; TP53; antiproliferative activity; diazaphenothiazines; intracellular apoptosis pathway.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Chemistry Techniques, Synthetic*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Humans
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • Phenothiazines / chemical synthesis
  • Phenothiazines / chemistry*
  • Phenothiazines / pharmacology*
  • Structure-Activity Relationship
  • Triazoles / chemistry*

Substances

  • Antineoplastic Agents
  • Phenothiazines
  • Triazoles